Local Production of Fatty Acid–Binding Protein 4 in Epicardial/Perivascular Fat and Macrophages Is Linked to Coronary Atherosclerosis

Furuhashi, Masato; Fuseya, Takahiro; Murata, Masaki; Hoshina, Kyoko; Ishimura, Shutaro; Mita, Tomohiro; Watanabe, Yuki; Omori, Akina; Matsumoto, Megumi; Sugaya, Takeshi; Oikawa, Tsuyoshi; Nishida, Jun‐ichi; Kokubu, Nobuaki; Tanaka, Marenao; Moniwa, Norihito; Yoshida, Hiroyuki; Sawada, Norimasa; Shimamoto, Kazuaki; Miura, Tetsuji

doi:10.1161/atvbaha.116.307225

Cited by 97 publications

(99 citation statements)

References 47 publications

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“…7-9 Previous studies using in vitro and in vivo experiments showed that FABP4 acts as an adipokine for the development of hepatic IR through increased hepatic glucose production, 7 suppression of cardiomyocyte contraction, 23 and development of atherosclerosis through induction of inflammatory responses, inhibition of endothelial nitric oxide synthase activity in endothelial cells and proliferation and migration of vascular smooth muscle cells. 9 Furthermore, a recent study demonstrated the possibility of a new strategy to treat metabolic disease by targeting serum FABP4 with a monoclonal antibody. 10 Circulating FABP4 may directly promote the progression of atherosclerosis in humans.…”

Section: Discussionmentioning

confidence: 99%

Circulating Fatty Acid-Binding Protein 4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication

Furuhashi

Yuda

Muranaka

et al. 2018

Circ J

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Background: Fatty acid-binding protein 4 (FABP4), which is expressed in both adipocytes and macrophages, is secreted from the cells and acts as an adipokine. An elevated circulating FABP4 level is associated with insulin resistance and atherosclerosis. Methods and Results:We investigated the causative association between FABP4 level and progression of atherosclerosis in subjects of the Tanno-Sobetsu Study, a population-based cohort. In 281 subjects without medication (male/female: 109/172) in the year 2010 or 2013, the carotid intima-media thickness (CIMT) assessed using carotid ultrasonography was significantly correlated with age, adiposity, blood pressure, renal dysfunction and levels of cholesterol, triglycerides, fasting glucose, HbA1c and FABP4 (r=0.331, P<0.001). Multiple regression analysis demonstrated that age, sex and FABP4 concentration were independent predictors of CIMT. A total of 78 (male/female: 29/49) of the 156 subjects in 2010 underwent carotid ultrasonography again in 2013. The change in CIMT each year during that 3-year period (mean ± SD: 3.8±22.3 µm/year) was positively correlated with basal levels of highsensitivity C-reactive protein (hsCRP) (r=0.231, P=0.046) and FABP4 (r=0.267, P=0.018) in 2010. After adjustment for age, sex and hsCRP level, the basal FABP4 level was independently associated with the change in CIMT per year.Conclusions: FABP4 concentration is an independent predictor of the progression of carotid atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Circulating Fatty Acid-Binding Protein 4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication

Furuhashi

Yuda

Muranaka

et al. 2018

Circ J

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“…Increased FABP4 expression has been reported in human epicardial adipose tissue from metabolic syndrome patients (Vural et al 2008), suggesting a paracrine effect on cardiac cells. Additionally, a recent study by Furuhashi and coworkers showed that FABP4 that is locally produced by epicardial/ perivascular fat and macrophages contributes to the development of coronary atherosclerosis (Furuhashi et al 2016), highlighting the potential paracrine role of this adipokine. Interestingly, Lamounier-Zepter showed that FABP4 induced a cardiodepressant effect in experimental models of isolated rat cardiomyocytes (LamounierZepter et al 2009, Lamounier-Zepter et al 2015, thus showing the first evidence of a cause-effect relationship between FABP4 and cardiomyocyte physiology.…”

Section: Fabp4 Cardiac Dysfunction and Hfmentioning

confidence: 99%

Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

Rodríguez-Calvo¹,

Girona²,

Alegret

et al. 2017

Journal of Endocrinology

100

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Obesity and ectopic fat accumulation in non-adipose tissues are major contributors to heart failure (HF) and cardiovascular disease (CVD). Adipocytes act as endocrine organs by releasing a large number of bioactive molecules into the bloodstream, which participate in a communication network between white adipose tissue and other organs, including the heart. Among these molecules, fatty acid-binding protein 4 (FABP4) has recently been shown to increase cardiometabolic risk. Both clinical and experimental evidence have identified FABP4 as a relevant player in atherosclerosis and coronary artery disease, and it has been directly related to cardiac alterations such as left ventricular hypertrophy (LVH) and both systolic and diastolic cardiac dysfunction. The available interventional studies preclude the establishment of a direct causal role of this molecule in CVD and HF and propose FABP4 as a biomarker rather than as an aetiological factor. However, several experimental reports have suggested that FABP4 may act as a direct contributor to cardiac metabolism and physiopathology, and the pharmacological targeting of FABP4 may restore some of the metabolic alterations that are conducive to CVD and HF. Here, we review the current knowledge regarding FABP4 in the context of HF and CVD as well as the molecular basis by which this protein participates in the regulation of cardiac function.

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“…The data are expressed as the mean ± standard error of the mean. (23,24). However, the exact molecular mechanisms remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism

Jiang

Zhang

et al. 2016

Molecular Medicine Reports

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Abstract. Hyperhomocysteinemia (HHcy) is an independent risk factor for the development of atherosclerosis (AS), according to overwhelming number of clinical and epidemiological studies. However, the underlying pathogenic molecular mechanisms by which HHcy promotes AS remain to be fully elucidated. Fatty acid binding protein 4 (FABP4) has been shown to be important in macrophage cholesterol trafficking. The objective of the present study was to determine whether homocysteine (Hcy) accelerates AS through regulating FABP4, and then mediates cholesterol accumulation in macrophages. Hcy concentrations of 0, 50, 100, 200 and 500 µM, and 100 µM Hcy+30 µM vitamin B 12 (VB 12 )+30 µM folic acid (FA) were respectively added to cultured THP-1 monocyte-derived macrophages for 24 h. The levels of FABP4, which acts as a key factor connecting cellular lipid accumulation to inflammation, were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in the macrophages. The present study used a nested touchdown methylation-specific PCR assay to detect the DNA methylation status of the FABP4 promoter region. In addition, the FABP4 gene fragment was inserted into the cloning vector, pcDNA3.1-EGFP, to construct the recombinant plasmid, pcDNA3.1-EGFP/FABP4, which was identified using restriction endonuclease digestion analysis and DNA sequencing. The pcDNA3.1-EGFP/FABP4 expression plasmid was transfected into THP-1 monocyte-derived macrophages, mediated by liposome reagent, following which the expression levels of FABP4 were detected using RT-qPCR and western blot analyses. The present study also determined the intracellular accumulation of total cholesterol in the macrophages. The results indicated that Hcy decreased the levels of FABP4 promoter methylation, but increased the mRNA and protein expression levels of FABP4 in the macrophages, compared with the control group (0 µM Hcy). However, no dose-dependent changes were observed with increasing concentrations of Hcy. The recombinant fluorescent eukaryotic expression vector, pcDNA3.1-EGFP/FABP4, was successfully constructed and effectively expressed in the THP-1 macrophages. The results also showed that FABP4 accelerated the accumulation of cholesterol in the macrophages. Taken together, the results of the present study suggested that FABP4 DNA hypomethylation induced by Hcy may be involved in the overexpression of FABP4, thereby inducing cholesterol accumulation in macrophages.

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Local Production of Fatty Acid–Binding Protein 4 in Epicardial/Perivascular Fat and Macrophages Is Linked to Coronary Atherosclerosis

Abstract: FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis.

Cited by 97 publications

References 47 publications

Circulating Fatty Acid-Binding Protein 4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication

Circulating Fatty Acid-Binding Protein 4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication

Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism

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